Despite numerous advances during the past decade, our understanding of how HIV-1 causes immunodeficiency is largely incomplete. Investigations of HIV-1 pathogenesis have also been hampered by a lack of a tractable animal model: with the exception of a recent report, HIV-1 inoculations of chimpanzees do not result in immunodeficiency. Because SIV, the close primate lentivirus relative of HIV-1, does induce an AIDS-like disease in Asian macaques and possesses a genomic organization similar to that of HIV-1, investigators have constructed SIV/HIV chimeric viruses (SHIVs) to address pathogenicity and vaccine issues related to the incorporated HIV-1 gene sequences. During the past year we have constructed a pathogenic SHIV and evaluated viral and cellular factors contributing to disease development. These include: 1) the use of virus derived directly from molecular clones rather than from serial animal-to-animal passage; 2) the screening of gene segments derived from HIV-1 isolates exhibiting T-cell line, macrophage, or dual tropic properties; 3) the testing of immunodeficiency-inducing properties of wild type and mutagenized HIV-1 and SIV nef genes; 4) the inoculation of three different macaque species; and 5) the size and properties of the challenge virus stock. CD8 cytotoxic T lymphocyte (CTL) responses are critical for the resolution of many viral infections. Although it has been inferred that the CTL response mediates the resolution of the primary HIV-1 infection, direct proof that CD8+ T lymphocytes are responsible for the decline of viremia during acute lentivirus infections and/or the control of virus spread/cell killing during chronic infection has not yet been obtained. To directly evaluate the role of CD8+ T lymphocytes during primary infection, a CD8 monoclonal antibody was parenterally administered to specifically deplete this lymphocyte subset prior to or during acute infections of rhesus macaques (Macaca mulatta) with a SIV/HIV (SHIV) chimeric virus. Animals receiving the anti-CD8 monoclonal antibody, developed a transient depletion of CD8 positive cells in both the peripheral blood and lymphoid tissues. When administered during primary SIV/HIV chimeric virus (SHIV) infections, the CD8 mAb caused marked elevations of plasma and cell-associated virus levels in both the peripheral blood and lymphoid tissues, and led to prolonged depletion of CD4 cells. Taken together, these results directly demonstrate that CD8+ T lymphocytes are actively involved in controlling the acute phase of primate lentivirus infections.